Drug combination studies of EZH2 inhibition combined with ATM, PI3-Kinase and CDK inhibitors in BRCA1-deficient breast tumors

Current targeted treatment options for BRCA1-deficient breast cancer are limited. BRCA1-mutant breast cancers frequently show a triple-negative phenotype and are associated with poor survival. At the cellular level, BRCA1 is important for DNA double-strand break repair through the homologous recombination pathway. Our group previously showed that EZH2 is significantly higher expressed in BRCA1-associated breast tumors. EZH2, a member of the Polycomb repressive complex 2, acts as an epigenetic suppressor through its trimethyltransferase activity of H3K27me3, a modification associated with a variety of pathways involved in stem cell self-renewal, cell cycle, cell differentiation, and cellular transformation. To further exploit EZH2 overexpression upon Brca1-deficiency, we designed a large-scale cell line-based drug synergy screen using EZH2 inhibitor GSK126 in combination with different inhibitors involved in DNA damage signaling or cell cycle regulation. We made use of cell lines that were derived from Brca1-deficient (K14Cre;Brca1fl/fl;Tp53fl/fl) and Brca1-proficient (K14Cre;Tp53fl/fl) murine mammary tumors. Our screen revealed synergistic sensitivity of Brca1-deficient cells to treatment with the ATM inhibitor AZD1390, PI3K inhibitor BKM120 or CDK inhibitor dinaciclib combined with GSK126. Further validations by a variety of functional in vitro experiments showed significant growth inhibition and increased levels of unrepaired DNA damage upon treatment with the combination of GSK126 and AZD1390 in Brca1-deficient breast cancer cells indicating drug synergy. These findings could be confirmed for combined treatment with GSK126/AZD1390 in our Brca1-deficient murine model which show a significant survival benefit. Combined treatment of GSK126 and BKM120, as well as GSK126 and dinaciclib for Brca1-deficient breast cancer cells also demonstrated in vitro activity but were found to be of additive character. In summary, we hereby describe a novel synergistic combination treatment of GSK126/AZD1390 for the treatment of BRCA1-deficient breast cancer

Growth hormone and aging: A challenging controversy

Although advanced age or symptoms of aging are not among approved indications for growth hormone (GH) therapy, recombinant human GH (rhGH) and various GH-related products are aggressively promoted as anti-aging therapies. Well-controlled studies of the effects of rhGH treatment in endocrinologically normal elderly subjects report some improvements in body composition and a number of undesirable side effects in sharp contrast to major benefits of GH therapy in patients with GH deficiency. Controversies surrounding the potential utility of GH in treatment of a geriatric patient are fueled by increasing evidence linking GH and cancer and by remarkably increased lifespan of GH-resistant and GH-deficient mice. Conservation of cellular signaling mechanisms that influence aging in organisms ranging from worms to mammals suggests that at least some of the results obtained in mutant mice are applicable to the human. We suggest that the normal, physiological functions of GH in promoting growth, sexual maturation and fecundity involve significant costs in terms of aging and life expectancy. Natural decline in GH levels during aging likely contributes to concomitant alterations in body composition and vigor but also may be offering important protection from cancer and other age-associated diseases

A game-theoretic approach to fairness for a distributed reservation-based medium access

[no abstract

Creditors\u27 Rights

Covers cases on time for filing claims under mechanics\u27 liens

Modeling strategic customers using simulations - with examples from airline revenue management

AbstractA condition for airline revenue management is the possibility of identifying and differentiating customer segments (refer to Chiang et al. (2007) for a state of the art). Traditionally, customer differentiation has been realized by the time of request in days before departure as well as by restrictions connected to the tickets sold. Customer segments have been regarded to be fixed over time, based on myopic customer behavior. With the market transparency increased through the Internet as well as the rise of no-frills offers and flat-rates, customer behavior has changed during the last decades. Strategic customer behavior describes a tendency to remember previous buying experiences, adapt expectations and observe the market over longer periods of time before deciding on what (and whether) to buy. The empirical consequences of strategic customer behavior for traditional as well as state-of-the-art revenue management have been little examined. A major reason for this is that measuring the degree of strategic versus myopic tendencies of demand in real customers is difficult and expensive. In this paper, we formulate a mathematical model of strategic customer behavior including parameters defining the propensity to delay buying as well as learning and communicating. We test the empirical consequences of our model using a stochastic simulation, in which customers act as agents deciding whether and when to buy. Thereby, we provide first results on how different ways of strategic behavior affect the success of methods of revenue management, highlighting the possible weaknesses and strengths of approaches when confronted with strategic customers. Of course, strategic customer behavior is not limited to airline revenue management. Useful models of strategic behavior as implemented in the simulation can be applied to analyze a wide range of situations: conditions for this transfer as well as examples are provided as part of the outlook

Consideration in Suretyship Contracts in Washington

The suretyship relation is a specialized form of contract and in order to be enforceable must satisfy all the requirements of contract formation, one of which is consideration. If this were always kept in mind and the cases analysed on the basis of technical contract rules, much of the difficulties and confusion found in the area would disappear. However, because of the tripartite nature of the suretyship transaction and of the circumstance that, at least historically, the surety generally did not derive any direct economic benefit from the transaction, lending his name and credit for reasons of blood ties or friendship, the basic nature of the transaction was often lost sight of by courts. This is most noticeable in the consideration area. Since people usually bargain for economic goods or services, which is almost invariably true of the principal contract in the suretyship situation, many cases tend to equate direct economic benefit with the technical concept of consideration